Kaposi's Sarcoma-Associated Herpesvirus (KSHV) is associated with several neoplastic diseases, including Kaposi's sarcoma and B cell lymphomas. In the general population, infection with KSHV is typically asymptomatic;disease is primarily associated with immunocompromise. KSHV is a member of the Gammaherpesvirinae subfamily of herpesviruses, which includes Epstein-Barr virus (EBV) and murine herpesvirus-68 (MHV-68). Like all herpesviruses, gammaherpesviruses alternate between lytic and latent cycles, and while latent infection with gammaherpesviruses is often associated with malignancy, periodic lytic reactivation is required for the virus to be maintained in the host, and represents the stage in the life cycle most visible to the immune system. A prominent feature of gammaherpesvirus lytic infection is the induction of a profound shutoff of host gene expression, believed to facilitate viral immune evasion and reduce competition with the host for resources. Host shutoff activity has been mapped to the gene product of ORF37, known as SOX, muSOX and BGLF5 in KSHV, MHV-68 and EBV, respectively. Despite the rapid and profound turnover of most cellular mRNAs, viral genes remain highly expressed, though the mechanism by which they evade destruction is as yet unknown. This proposal aims to discern how viral transcripts escape host shutoff, determining both the protective elements inherent to the transcript and which, if any, additional viral genes are required for protection. This will not only clarify an important aspect of the viral lytic cycle, it will also further our understanding of the regulation of RNA turnover in cells. PUBLIC HEALTH RELEVANCE: Our understanding of the life cycle of cancer-causing gammaherpesviruses is limited. We will attempt to elucidate the means by which these viruses actively replicate while subverting the immune response. Identifiying the mechanisms by which these viruses hijack host cells, replicate and evade the immune system will identify weaknesses that may be exploited in developing treatments and vaccines.